Original Article Diagnostic value of bone-specific alkaline phosphatase metastases: a meta-analysis

Int J Clin Exp Med 2015;8(10):17271-17280
www.ijcem.com /ISSN:1940-5901/IJCEM0012164
Original Article
Diagnostic value of bone-specific alkaline phosphatase
in lung carcinoma patients with bone
metastases: a meta-analysis
Qing-Tao Zhao1, Zhao-Xu Yang2*, Lei Yang3*, Dong Xing2, Jing-Chao Wei2, Wen-Yi Li2
Departments of 1Thoracic Surgery, 2Orthopedics, Hebei General Hospital, Shijiazhuang 050051, Hebei, P. R.
China; 3Department of Pediatrics, Bethune International Peace Hospital of Chinese PLA, Shijiazhuang 050082,
Hebei, P. R. China. *Co-first authors.
Received June 30, 2015; Accepted October 9, 2015; Epub October 15, 2015; Published October 30, 2015
Abstract: Aim and Backgrounds: The accurate diagnosis of lung carcinoma patients with bone metastases is crucial
for therapy and the prevention of complications. We performed a systematic review and meta-analysis to evaluate
the diagnostic value of serum bone-specific alkaline phosphatase (BALP) in lung carcinoma patients with bone metastases. Methods: Such databases as PubMed, Embase, Cochrane Library, Web of Science, Ovid, BioMed Central,
Biosis previews and four Chinese databases (Chinese Biomedical Literature Database-disc (CBM), Chinese National
Knowledge Infrastructure (CNKI), Technology of Chongqing (VIP) and Wan Fang DATA) were retrieved on computer,
and the relevant journals were also manually searched to collect the trials on BALP in diagnosis of lung carcinoma
patients with bone metastases. The meta-analysis was conducted by using Meta-Disc 1.4 software. Results: A total
of 8 studies were included, and there were 848 lung carcinoma patients diagnosed by gold standard, patients were
divided into two groups: 419 cases with bone metastases and 429 cases without bone metastases. The metaanalysis showed that, the pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR) was 0.48 [95% CI (0.43 to 0.53)], 0.86 [95% CI (0.82 to 0.89)],
3.14 [95% CI (2.47 to 3.99)], 0.62 [95% CI (0.56 to 0.68)], 6.66 [95% CI (4.62 to 9.60)] respectively. And the AUC
of SROC was 0.78, (Q*=0.72). Conclusion: BALP has greater diagnostic value in detecting lung carcinoma patients
with bone metastases. However, further large scale studies are required to confirm the predictive value.
Keywords: Lung carcinoma, bone metastases, BALP, meta-analysis
As the second leading cancer type for the estimated new cancer cases, lung carcinoma represents the major cause of cancer death in
both females and males [1]. Bone metastasis
can be found frequently in lung carcinoma [1,
2]. It is reported as 24-40% in clinical studies
and 36-40% in autopsy series [3, 4]. Lung carcinoma frequently develops bone metastases
in advanced stages of disease [5]. The main
symptoms of bone metastasis include severe
pain, pathological fractures, spinal cord compression, hypercalcemia, anemia and so on [6,
7]. But up to 20-25% of patients are asymptomatic [7]. These skeletal-related events have
been associated with reduced quality of life
and reduced overall and median survival, so
the early diagnose of bone metastasis and
effective therapy could be initiated timely and
improvement of life quality and treatment to the
patients may be achieved [8, 9].
Diagnosis of bone metastasis is usually performed initially with plain radiography or computed tomography (CT) or magnetic resonance imaging (MRI) or bone scintigraphy screening and confirmed by whole body bone scan by
single-photon emission computed tomography
(SPECT) [10-12]. However, they have very low
sensitivity in detecting bone micro metastasis
[12]. Bone scan is excellent for whole-body
screening and can detect micro metastasis of
bone metastasis [13, 14]. However, it can give
false-negative results in lytic bone lesions and
the risk of radioisotope exposure. Due to SPECT
have high price and radioactivity, it is not a necessary recommendation for newly diagnosed
patients [14].
Diagnostic value of BALP in LC patients with BM: a meta-analysis
Figure1. The study selection and inclusion process.
In contrast, the detection of serum bone metabolic markers is cheap and easy to perform,
and may assist in the early diagnosis and assessment of therapeutic results in bone metastasis [15-17]. BALP is the bone-specific isoform
of alkaline phosphatase, which originates from
many tissues, but primarily the liver and bone
[18, 19]. BALP is a tetrameric glycoprotein
found on the cell surfaces of osteoblasts [18,
19]. The exact function of BALP remains unknown. However, it has been suggested that it
might play a role in mineralization of newly
formed bone [15].
There have been studies reporting the use of
serum BALP as a serum marker for bone metastases in patients with lung carcinoma, but the
results are heterogeneous and even conflicting
[20-22]. The practical value of these markers
has yet to be fully evaluated. The objective of
the present review was to synthesize and analyze the results from systematic selection of
research papers that evaluated the diagnostic
accuracy of serum BALP by directly diagnosis of
bone metastasis in patients with lung carcinoma.
Search strategy
A comprehensive systematic literature review
of original researches studying the diagnostic
accuracy test accuracy of BALP in lung carcinoma patients with bone metastases was performed searching the following electronic databases through February 15th 2015: PubMed,
Embase, Cochrane library, Web of science, Ovid, BioMed central, Biosis previews and four
Chinese databases (CBM, CNKI, VIP and Wan
fang DATA). In addition we conducted supplementary searches in the references of the
retrieved articles. Titles and abstracts were
reviewed for relevance. Relevant prospective or
retrospective cohort or case-control studies
were included in the meta-analysis. Subject
headings and keywords used in the search process included the following: “bone-specific alInt J Clin Exp Med 2015;8(10):17271-17280
Diagnostic value of BALP in LC patients with BM: a meta-analysis
Table 1. Summary of the diagnostic results of the included studies
Germany CLIA
Turkey ELISA
Year Country
Aruga A
Alatas F
Ebert W
Kong QQ
Lumachi F
Bayrak SB
Tang C
Xin Y
EIA: Enzyme immunoassay; CLIA: Chemiluminescence immunoassay; ECLI: Electrochemiluminescence immunoassay; ELISA: Enzyme-linked immunosorbent assay; TP:
True positive; FP: False positive; TN: True negative; FN: False negative; SEN: Sensitivity; SPE: Specificity.
Inclusion criteria
Studies were considered eligible for inclusion if they met
the following criteria: I) Study
design. Observational studies
(cohort or case-control studies). II) Population. Lung carcinoma patients with bone metastases, or without bone metastases. III) Diagnostic test.
Serum BALP in lung carcinoma patients. IV) Reference test. The following reference tests were considered eligible:
radiologic examination (X-ray,
CT, MRI), histological examination, etc.
Exclusion criteria
Studies were excluded from
the meta-analysis for the following reasons: I) Duplicate
publication; II) No human studies; III) Necessary data could
not be obtained.
Study selection
All the studies were reviewed by two reviewers independently based on titles and
abstracts, and then the full texts of potentially eligible studies were retrieved for further assessment. We resolved
disagreements by reaching a
consensus through discussion.
Data abstraction
Figure 2. Presentation of QUADAS-2 results.
kaline phosphatase”, “BAP”, “BALP”, “BSAP”,
“sBAP”, “lung cancer”, “lung carcinoma” and
“lung neoplasms”. The controlled vocabulary
search terms for different databases are not
identical. Therefore, search strategies need to
be customized for each database.
The following data was extracted from the included studies by two reviewers independently: authors, year of publication, journal, study design, number of eligible patients, and reference test for the analysis of SEN
and SPE (the number of true positive (TP), false
negative (FN), true negative (TN) and false positive (FP) results) for comparison of lung carcinoma patients diagnosed with bone metastases vs. control. Any disagreements were re-
Int J Clin Exp Med 2015;8(10):17271-17280
Diagnostic value of BALP in LC patients with BM: a meta-analysis
tion when in doubt. The MetaDiSc 1.4 (XI Cochrane Colloquium, Barcelona, Spain) was
used to perform all data analysis. The following indexes of
test accuracy were computed for each study: SEN, SPE,
PLR, NLR, DOR and generate the bivariate SROC curve
[25]. The DOR value ranges
from 0 to infinity, with higher
values indicating higher accuracy levels [26]. Data were
presented as forest plots and
receiver operating characteristic curves. Forest plots display the SEN and SPE of individual studies with the corresponding 95% confidence
Figure 3. Summary receiver operating characteristic (SROC) curve for BALP
intervals. The receiver operatin the diagnosis of Lung carcinoma patients with bone metastases in the 8
ing characteristic curves shincluded studies.
ow individual study data points with size proportional to
solved through consultation with the third restudy weight [24, 27]. The area under the AUC
represents an analytical summary of the test
performance and illustrates the trade-off beAssessment of methodological quality
tween SEN and SPE [24, 27]. The chi-squarebased Q test and the inconsistency index I2
The methodological quality of the included
were used to detect statistically significant hetstudies was independently assessed by two
erogeneity across studies. When a significant Q
authors, using the Quality Assessment of Diatest (P<0.05 or I2>50%) indicated heterogenegnostic Accuracy Studies 2 (QUADAS-2) tool
ity among studies, the random-effect model
[23], which consists of four domains: patient
(DerSimonian-Laird method) was conducted for
selection, index test, reference standard, and
the meta-analysis to calculate the pooled SEN,
flow and timing. QUADAS-2 is an updated verSPE, and other related indexes of the studies;
sion of this evidence-based quality tool. All
Otherwise, the fixed-effect model (Mantel-Hadomains are assessed for risk of bias and the
enszel method) was chosen. Chi-square test
first three domains are assessed for applicabilwas used to detect statistically significant hetity by indicating a “low”, “unclear”, or “high” raterogeneity across studies. Additionally, we also
ing. This tool helps to evaluate the principal
calculated the Spearman correlation coeffimethodological risk of bias in systematic revicients. A strongly positive rank-correlation coefews of diagnostic test accuracy [24]. Specific
ficient and a value of, 0.05 are indicative of a
coding instructions adapted for this review will
significant threshold effect.
be included for the reviewers. In case of doubt,
a third and fourth reviewer were consulted.
Data analysis
Search results
Standard methods recommended for metaanalysis of diagnostic accuracy were used. The
number of TP, TN, FP and FN were retrieved
from each article by two investigators independently and entered into an excel datasheet [24,
25]. Discordant findings were assessed in a
joint approach and authors asked for verifica-
A total of 278 titles and abstracts were preliminarily reviewed, of which 8 studies were available for the meta-analysis, including 848 lung
carcinoma patients who received serum BALP
tests [21, 22, 28-33]. Figure 1 shows a flow diagram of the selection process. The characteristics of each study are shown in Table 1.
Int J Clin Exp Med 2015;8(10):17271-17280
Diagnostic value of BALP in LC patients with BM: a meta-analysis
Figure 4. Forest plot for the diagnostic odds ratio (DOR) of BALP to diagnose Lung carcinoma patients with bone
metastases. DOR (diagnostic odds ratio)=6.66 (95% CI, 4.62-9.60).
Figure 5. Forest plot for the sensitivity of BALP to diagnose Lung carcinoma patients with bone metastases. Sensitivity=0.48; (95% CI, 0.43-0.53).
Assessment of methodological quality
When using the QUADAS-2 tool to review the
eight included articles, it was determined that
three studies [22, 29, 32] had low risk of bias
and low concern regarding applicability. Three
studies [21, 28, 33] were found to be at risk for
bias, but had low concerns regarding applicability. The final two studies [30, 31] were judged to
be at risk of bias and as having concerns
regarding applicability (Figure 2).
The corresponding SROC (Figure 3) shows an
AUC of 0.78 with standard error=0.02, and the
pooled diagnostic accuracy (Q*) was 0.72 with
standard error=0.02, indicating high overall
accuracy of BALP for the diagnosis of lung carcinoma patients with bone metastases.
The Spearman rank correlation coefficient was
0.64 (P=0.09), confirming that the variability
across these studies could not be explained by
differences in the diagnostic threshold.
The pooled DOR
Significant heterogeneity among the studies
was not detected (Cochran Q statistic=5.38;
P=0.61). A Forest plot for the DOR of BALP for
the diagnosis of lung carcinoma patients with
bone metastases was 6.66 with a corresponding 95% CI of 4.62-9.60, as shown in Figure 4.
Int J Clin Exp Med 2015;8(10):17271-17280
Diagnostic value of BALP in LC patients with BM: a meta-analysis
Figure 6. Forest plot for the specificity of BALP to diagnose Lung carcinoma patients with bone metastases. Specificity=0.86 (95% CI, 0.82-0.89).
Figure 7. Forest plot for the positive likelihood ratio (PLR) of BALP to diagnose Lung carcinoma patients with bone
metastases. PLR (positive likelihood ratio)=3.14 (95% CI, 2.47-3.99).
The pooled sensitivity and specificity
Significant heterogeneity among the studies was detected (SEN: chi-square=54.34, P=
0.00), Figure 5). SPE: chi-square=20.31, P<
0.0049, Figure 6). The SEN ranged from 22% to
89% (pooled, 48%; 95% CI, 43-53%), whereas
SPE ranged from 44% to 100% (pooled, 86%;
95% CI, 82-89%).
The pooled PLR and NLR
Significant heterogeneity among the studies
was also detected in the PLR (Cochran Q statis-
tic=20.30, P=0.01, Figure 7). However, no significant heterogeneity was found in the NLR
(Cochran Q statistic=19.40, P=0.01, Figure
8). The pooled PLR was 3.14 (95% CI, 2.473.99), and the pooled NLR was 0.62 (95% CI,
Solid circles represent each study included in
the meta-analysis. The size of each study is
indicated by the size of the solid circle. The
regression SROC curve summarizes the overall diagnostic accuracy. AUC (area under the
curve)=0.78, Q*=0.72.
Int J Clin Exp Med 2015;8(10):17271-17280
Diagnostic value of BALP in LC patients with BM: a meta-analysis
Figure 8. Forest plot for the negative likelihood ratio (NLR) of BALP to diagnose Lung carcinoma patients with bone
metastases. NLR (negative likelihood ratio)=0.62 (95% CI, 0.56-0.68).
The early diagnosis of bone metastases may
bring improvements of life quality and treatment to the lung carcinoma patients [1, 34,
35]. More and more attention has been paid to
the improvement of early diagnosis of bone
metastases [34]. The well-recognized screening method SPECT is not recommended for
patients without evidence of bone pain, and it
does not suit for continuous monitoring due to
its high price and radioactivity [36, 37]. The
increasing incidence of bone metastases worldwide has sparked a new interest in serum
markers [20, 38, 39]. A number of new biochemical markers of bone turnover have been
extensively studied in the clinical diagnosis [38,
BALP is considered marker of matrix maturation (middle phase) and mineralization (late
phase), respectively, in the phenotypic developmental sequence of osteoblasts [18, 40]. In
particular, serum BALP has been increasingly
used for the diagnosis of bone metastasis in
patients with lung carcinoma [41]. In the same
study, serum levels of BALP were significantly
increased in lung carcinoma patients with bone
metastases compared with those without bone
metastases [21, 28-33]. In some other studies,
BALP levels did not differ between the groups
with and without metastasis but were found to
be significantly higher than in the control group
[22, 41]. Therefore, it was imperative to pool
the results of individual studies to evaluate the
diagnostic value of this method via meta-analysis. To evaluate the diagnostic and clinical valve
of BALP a serological marker, we conducted
this meta-analysis to provide a comprehensive
and up-to-date analysis of the feasibility and
accuracy of BALP for the diagnosis of bone
metastases. As far as we know, this is the first
meta-analysis about the diagnostic value of
BALP for bone metastases.
In this meta-analysis, we show that the pooled
SEN and SPE are 0.48 [95% CI (0.43 to 0.53)]
and 0.86 [95% CI (0.82 to 0.89)] respectively.
Thus, BALP enjoys it has higher SEN and SPE
compared to conventional serum alkaline phosphatase (ALP) (SEN of 26.7%) and bone scan
(SPE of 44.1%) [37]. It has higher sensitivity
and SPE in effectively diagnosing of bone
metastases. Glas et al. [26] found that the DOR
combines the strengths of SEN and SPE as
prevalence in dependent indicators and has
the advantage of accuracy over a single indicator. The value of DOR ranges from 0 to infinity
with higher values indicating better discriminatory test performance [22]. The DOR value of
6.66 indicates that the BALP could be a useful
biomarker for bone metastases patients’ diagnosis. AUC is calculated to evaluate accuracy of
the selected indicator, and SROC is usually
used to summarize overall test performance
[42, 43]. To demonstrate excellent accuracy,
the valve of AUC should be more than 0.97. An
AUC of 0.93 to 0.96 is considered to be very
good and 0.75 to 0.92 is good [38, 39]. In these
studies, we show that BALP demonstrates good
Int J Clin Exp Med 2015;8(10):17271-17280
Diagnostic value of BALP in LC patients with BM: a meta-analysis
accuracy in the diagnosis of lung carcinoma,
with an area under the ROC curve of 0.78.
Overall, although the SEN is compromised,
BALP has a good SPE in the diagnosis of bone
metastases. The PLR and NLR are more meaningful indicators of diagnostic accuracy. A good
diagnostic test may have high PLR (PLR>5) and
low NLR (NLR<0.2) [24, 44]. However, the PLR
and NLR value of this study did not meet these
thresholds. In this meta-analysis, a PLR value
of 3.14 demonstrated that lung carcinoma
patients with bone metastases had approximately 3.14 times higher chance of testing
positive than patients without bone metastases, and this was relatively high for clinical purposes. On the other hand, an NLR value of 0.62
revealed that a patient with bone metastases
had a 62% chance of testing negative, and this
method is therefore not sensitive enough to
rule out bone metastases in the case of a negative test. These results suggest that a substantial proportion of patients might be incorrectly
classified according to BALP. Based on the current pooled evidence, using BALP will help to
diagnose bone metastases, but may not fully
replace other routine diagnostic methods such
as CT, MRI, bone scintigraphy screening and
SPECT, which have been used for the diagnosis
of bone metastases.
Heterogeneity is a potential problem when
interpreting the results for all meta-analysis
[24, 26]. One of the primary causes of heterogeneity in test accuracy studies is threshold
effect, which arises when differences in sensitivities and specificities occur due to different
thresholds used in different studies to define a
positive or negative test result [24, 26]. As different thresholds were used among the 8 studies, we used the Spearman correlation coefficient to analyze the threshold effect. The Spearman correlation coefficient of sensitivity
and 1-specificity is 0.64 (P=0.09), which indicates that the variability across these studies
could not be explained by differences in the
diagnostic threshold. We speculated that the
heterogeneity was attributed to the ethnicity,
etiology, assay methods and different geographical locations. We speculated that the limited
number of eligible studies was the main factor
that made subgroup analysis not possible.
However, these hypotheses need to be investigated in the future study.
It is well recognized that the quality of special
clinical tests can influence the outcome of a
diagnostic accuracy study [45]. Both prospective and retrospective guidelines are designed
to allow the clinician/researcher to differentiate
the quality of study designs thus further refining which tests are proper for use in clinical
practice [24, 45]. Nevertheless, combining the
results of multiple studies increases the diagnostic accuracy of outcome estimates to the
levels that are largely unachievable by standalone studies [24]. Furthermore, combining
results from multiple studies can detect homogeneity among their results making estimated
diagnostic accuracy generalizable to other clinics [24, 26]. Risk of publication bias assessment was considered inappropriate and not
meaningful. Application among meta-analysis
with small number of studies (n<10) yields low
statistical power [26]. Therefore, publication
bias assessment was not performed. Despite
these limitations, homogeneous study results
were observed for most parameters relating to
the diagnostic accuracy of BALP. Therefore, we
feel confident that the estimated parameters of
diagnostic accuracy approach the levels achieved in a clinical setting.
This meta-analysis had some limitations. First,
we only included eight studies that have a
smaller number of cases. Therefore, the results
of the trials in a pooled analysis were not
robust. More studies are needed for future
analyses. Second, we did not calculate the
some covariates because sufficient raw data
was not available from the selected articles.
These probable covariates included tumor type,
ethnicity, histology, assay methods and so on.
Third, this meta-analysis was based on published studies; the exclusion of unpublished
data is generally associated with an overestimation of the true effect, thus resulting in a
publication bias.
The present meta-analysis demonstrated that
BALP has a role in the diagnosis of bone metastases. The results of this diagnostic method
should be interpreted in parallel with clinical
findings and other conventional tests. We
believe that evaluation of the present diagnostic method will provide evidence to aid DOC in
diagnosing bone metastases. However, it would
not be recommended for using independently.
Due to the limitations of the present meta-analysis, additional high-quality original studies are
required to confirm the predictive value.
Int J Clin Exp Med 2015;8(10):17271-17280
Diagnostic value of BALP in LC patients with BM: a meta-analysis
Disclosure of conflict of interest
Address correspondence to: Wen-Yi Li, Department
of Orthopedics, Hebei General Hospital, 348 West
He-Ping Road, Shijiazhuang 050051, Hebei Province, P. R. China. Tel: +86 0311 85988160; Fax: +86
031185988574; E-mail: hbghgk@163.com
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